Liposomes have been well established as an effective drug delivery system, due to simplicity of their preparation and unique characteristics. However conventional liposomes are unsuitable for the on-demand content release, which limits their therapeutic utility. Here we report X-ray-triggerable liposomes incorporating gold nanoparticles and photosensitizer verteporfin. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the efficiency of gene silencing in vitro and increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray-triggered liposomes. Importantly, our X-ray-mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation.

Nanomaterials have become promising platforms in the field of drug and gene delivery, offering unique advantages over traditional therapeutic approaches. Their tunable physicochemical properties enable improved pharmacokinetics and therapeutic performance. A wide range of nanocarriers, including lipid‐based, polymer‐based, and hybrid systems, have been rapidly developed and are attracting increasing attention in both preclinical and clinical research. However, despite promising preclinical outcomes, these systems still encounter critical challenges in achieving precise delivery to specific tissues, cells, and intracellular compartments. This review provides a comprehensive assessment of recent advances in the design and application of nanocarriers for targeted delivery, with emphasis on strategies designed for nuclear targeting. In the context of nuclear targeting, it explores passive approaches involving modulation of particle size, morphology, and surface charge, alongside active targeting strategies incorporating nuclear localization signals and other ligands. In addition to highlighting progress, the review examines the limitations associated with delivery efficiency, off‐target effects, and barriers to clinical translation. By addressing both advances and ongoing challenges, this review provides valuable insights into the design and engineering of targeted nanocarriers. These developments are crucial for unlocking the full potential of precision nanomedicine.

Introduction: The depth limitation of conventional photodynamic therapy (PDT) with visible electromagnetic radiation represents a challenge for the treatment of deep-seated tumors. Materials and methods: To overcome this issue, we developed an X-ray-induced PDT system where poly(lactide-co-glycolide) (PLGA) polymeric nanoparticles (NPs) incorporating a photosensitizer (PS), verteporfin (VP), were triggered by 6 MeV X-ray radiation to generate cytotoxic singlet oxygen. The X-ray radiation used in this study allows this system to breakthrough the PDT depth barrier due to excellent penetration of 6 MeV X-ray radiation through biological tissue. In addition, the conjugation of our NPs with folic acid moieties enables specific targeting of HCT116 cancer cells that overexpress the folate receptors. We carried out physiochemical characterization of PLGA NPs, such as size distribution, zeta potential, morphology and in vitro release of VP. Cellular uptake activity and cell-killing effect of these NPs were also evaluated. Results and discussion: Our results indicate that our nanoconstructs triggered by 6 MeV X-ray radiation yield enhanced PDT efficacy compared with the radiation alone. We attributed the X-ray-induced singlet oxygen generation from the PS, VP, to photoexcitation by Cherenkov radiation and/or reactive oxygen species generation facilitated by energetic secondary electrons produced in the tissue. Conclusion: The cytotoxic effect caused by VP offers the possibility of enhancing the radiation therapy commonly prescribed for the treatment of cancer by simultaneous PDT.

Liposomes are an effective gene and/or drug delivery system, widely used in biomedical applications including gene therapy and chemotherapy. Here, we designed a photo-responsive liposome (lipVP) loaded with a photosensitizer verteporfin (VP). This photosensitizer is clinically approved for photodynamic therapy (PDT). LipVP was employed as a DNA carrier for pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) gene knockdown in PC12 cells. This has been done by incorporating PAC1R antisense oligonucleotides inside the lipVP cavity. Cells that have taken up the lipVP were exposed to light from a UV light source. As a result of this exposure, reactive oxygen species (ROS) were generated from VP, destabilizing the endolysosomal membranes and enhancing the liposomal release of antisense DNA into the cytoplasm. Endolysosomal escape of DNA was documented at different time points based on quantitative analysis of colocalization between fluorescently labeled DNA and endosomes and lysosomes. The released antisense oligonucleotides were found to silence PAC1R mRNA. The efficiency of this photo-induced gene silencing was demonstrated by a 74% ± 5% decrease in PAC1R fluorescence intensity. Following the light-induced DNA transfer into cells, cell differentiation with exposure to two kinds of PACAP peptides was observed to determine the cell phenotypic change after PAC1R gene knockdown.